PDE is an enzyme which acts as a catalyst in hydrolysis of cyclic adenosine 3',5'-phosphate (cAMP) or cyclic guanosine 3',5'-phosphate (cGMP) into 5'-monophosphate. cAMP and cGMP are produced from ATP and GTP, respectively, following activation of adenylate cyclase or guanylate cyclase in response to a hormone or chemical transmission substance, and work as intracellular second messengers. PDE inhibitory agents block the activity of PDE to increase the amounts of intracellular cAMP and cGMP, to thereby suppress cellular response. At present, PDE is known to have type I to type VIII isozymes. These are found in the central nervous system, circulatory system, respiratory system, digestive system, reproductive system, and blood cell system. The distribution of these isozymes differs according to the tissue. This suggests that a PDE-isozyme-specific inhibitor may increase the amount of cAMP in certain specific tissue.
In recent years, considerable efforts have been devoted to research and development of highly specific PDE isozyme inhibitors. For example, attempts have been made to develop drugs that exhibit organ specificity attributable to localization of respective isozymes. As a result of such attempts, PDE IV is considered to be a potential agent effective for both asthmatic attack and chronic respiratory tract inflammation, due to the facts that PDE IV is present predominantly in the airway tissue or inflammatory cells, such as eosinocytes and neutrophilic leukocytes, which are intimately related to asthmatic symptoms and that drugs that inhibit the action of PDE IV exhibit bronchodilatation action as well as inhibitory action against activation of inflammatory leukocytes. Thus, active studies have been performed worldwide focusing on development of a selective inhibitor against PDE IV as a new remedy for bronchial asthma.
PDE IV, which also exists in the central nervous system, is expected to improve memory and mitigate anxiety, based on the consideration that a rolipram, a selective PDE IV inhibitor, specifically localizes in the brain tissue to increase noradrenergic nervous transmission on a synapse or post-synapse level in response to an increased amount of cAMP, which is a second messenger of noradrenalin.
TNF-.alpha. is a cytokine produced by an activated macrophage. Although TNF-.alpha. was first discovered to be a factor which induces hemorrhagic necrosis in a tumor site, it is now recognized as a mediator which widely participates in inflammatory reactions and the immune mechanism. Excessive production of TNF-.alpha., however, induces disorders in tissue to cause a variety of pathological conditions. Rapid release of TNF-.alpha. induced by intracellular toxins is responsible for the lethality.
TNF-.alpha. promotes production of platelet-activating factor (PAF), a variety of inflammatory arachidonic metabolites, and activated oxygen. Moreover, it induces production of interleukin (IL)-1, IL-6, and IL-8. As is understood from this, excessive production of TNF-.alpha. aggravates inflammatory reactions and, in the case of chronic inflammatory diseases such as rheumatism, osteoporosis, and terminal cancers, results in a persistence of complication of diseases, in which the concentrations of these cytokines are maintained consistently so as exacerbate the symptoms. Accordingly, in pathological conditions in which TNF-.alpha. is produced excessively, control of its release is strongly sought by clinicians.
So far, molecular design of a selective PDE IV inhibitor has not yielded satisfactory results, and therefore limitation is imposed on use of the selective PDE IV inhibitor. Theophylline, which is a xanthine-based drug widely used by clinicians as a therapeutic agent for the treatment of bronchial asthma, exhibits bronchodilating action stemming from the adenosine antagonizing action and PDE inhibitory action. However, theophylline sometimes causes adverse side effects in the circulatory system and central nervous system, as it inhibits PDE non-selectively. Thus, the safety range of theophylline is rather narrow. Rolipram and Ro20-1724 selectively inhibit PDE IV at a potency 100 times that at which they inhibit other PDE isozymes. However, the inhibitory power itself is not significant, imposing limitations on applicable diseases.
TNF-.alpha. production inhibitors include antiphlogistic steroids, antihistaminic agents, PAF antagonists, and active-oxygen quencher. However, these are nonspecific inhibitors with either weak power or, when their power is strong, with low tissue specificity, thus limiting their methods of use. Moreover, protease inhibitors have recently been reported to be specific TNF-.alpha. production inhibitors. The protease inhibitors are peptide derivatives and have not yet been extensively studied with regard to administration methods, etc.
Accordingly, the present invention is directed to the provision of therapeutics for a variety of diseases based on the selective PDE IV inhibitory action; the provision of therapeutics for a variety of diseases based on the TNF-.alpha. production inhibitory action; and the provision of drugs for the prevention and treatment of a wide variety of inflammatory diseases and autoimmune diseases, which drugs are designed based on concurrent actions of these two actions and are endowed with enhanced effects, higher specificity, and higher safety.